title: Fluoroquinolone and quinazolinedione activities against wild-type and gyrase mutant strains of Mycobacterium smegmatis.
abstract: Quinazolinediones (diones) are fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV. To assess activity against mycobacteria, C-8-methoxy dione derivatives were compared with cognate fluoroquinolones by using cultured Mycobacterium smegmatis. Diones exhibited higher MIC values than fluoroquinolones; however, MICs for fluoroquinolone-resistant gyrA mutants, normalized to the MIC for wild-type cells, were lower. Addition of a 3-amino group to the 2,4-dione core increased relative activity against mutants, while alteration of the 8-methoxy group to a methyl or of the 2,4-dione core to a 1,3-dione core lowered activity against mutants. A GyrA G89C bacterial variant was strikingly susceptible to most of the diones tested; in contrast, low susceptibility to fluoroquinolones was observed. Many of the bacteriostatic differences between diones and fluoroquinolones were explained by interactions at the N terminus of GyrA helix IV revealed by recently published X-ray structures of drug-topoisomerase-DNA complexes. When lethal activity was normalized to the MIC in order to minimize the effects of drug uptake, efflux, and ternary complex formation, a 3-amino-2,4-dione exhibited killing activity comparable to that of a cognate fluoroquinolone. Surprisingly, the lethal activity of the dione was inhibited less by chloramphenicol than that of the cognate fluoroquinolone. This observation adds the 2,4-dione structural motif to the list of structural features known to impart lethality to fluoroquinolone-like compounds in the absence of protein synthesis, a phenomenon that is not explained by X-ray structures of drug-enzyme-DNA complexes.
authors.affiliation: Public Health Research Institute, Department of Microbiology and Molecular Genetics, New Jersey Medical School, UMDNJ, 225 Warren St., Newark, NJ 07103, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Malik
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Marks
authors.forename: Arkady
authors.initials: A
authors.lastname: Mustaev
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhao
authors.forename: Kalyan
authors.initials: K
authors.lastname: Chavda
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kerns
authors.forename: Karl
authors.initials: K
authors.lastname: Drlica
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D027081:DNA Gyrase / Q000235:genetics*; D024841:Fluoroquinolones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D052999:Quinazolinones / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D052999:Quinazolinones; D027081:DNA Gyrase